Thrombospondin induces the migration of human melanoma and carcinoma cells. Using a modified Boyden chamber assay, tumor cells migrated to a gradient of either soluble thrombospondin (chemotaxis) or substratum bound thrombospondin (haptotaxis). A series of human melanoma and carcinoma cells exhibited different levels of response when compared for their relative motility stimulation by thrombospondin haptotaxis versus chemotaxis. Human A2058 melanoma cells which exhibit a strong haptotaxic and chemotaxic response to thrombospondin were used to study the structural domains of thrombospondin required for the response. Using fragments of thrombospondin and monoclonal antibodies to the COOH and NH2 domains, it was found that the COOH domain mediated haptotaxis and the NH2 domain mediated chemotaxis. Pertussis toxin treatment inhibited chemotaxis but not haptotaxis implicating separate G protein transducer systems for each type of motility.